Process for lysergic acid hydrazides



United States Patent C) 3,239,530 PROCESS FOR LYSERGIC ACID HYDRAZEDES Albert Hofmann, Bcttmingen, Jiirg Rutschmann, Oberwil, Basel-Land, Paul Stadler, Biel-Benken, and Franz Troxler, Bottmingen, Switzerland, assignors to Sandoz Ltd, Basel, Switzerland No Drawing. Filed Jan. 13, 1964, Ser. No. 337,163 3 Claims. (Cl. 260-4855) N-CHs wherein R signifies a member selected from the group consisting of hydrogen, alkyl containing from 1 to 4 carbon atoms, alkenyl containing from 3 to 4 carbon atoms, and benzyl. The molecular asymmetry of the compounds resides in the carbon atom marked with a dot in Formula I, the hydrogen atom attached to it lying above the plane of the paper in the D-series.

The present invention also relates to new compounds of the Formula I, wherein R signifies a member of the group consisting of alkyl containing from 1 to 4 carbon atoms inclusive, alkenyl containing from 3 to 4 carbon atoms, and benzyl, and their physiologically acceptable acid addition salts.

The process consists of reacting an optically active lysergic acid derivative of the formula:

wherein R has the above significance and R signifies a member selected from the group consisting of alkoxy containing from 1 to 4 carbon atoms inclusive, amino (including a member selected from the group consisting of primary amino, alkylamino, hydroxyalkylamino, in which the alkyl portion contains from 1 to 4 carbon atoms inclusive), or a member selected from the group consisting of tripeptides of the type of the natural ergot alkaloids, with excess hydrazine in the presence of at least one equivalent of acid for every mol of compound II, the expression excess meaning that the number of mols of hydrazine must be at least equal to the number of equivalents of =acid-I-2. The acid used for the process may be selected from the inorganic or organic acids of sufiicient strength, e.g. with a pK value smaller than 5.

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Examples of acids which may be used are inorganic acids, such as hydrochloric, hydrobromic or sulfuric acid; alkylor arylsulfonic acids, for example methanesulfonic 0r benzenesulfonic acid; aliphatic and aromatic carboxylic acids such as formic, acetic or benzoic acid.

The acid may be added to the reaction mixture as such or, simpler, by using a preformed acid addition salt of the alkaloid or of part of the hydrazine.

The use of a solvent is as a rule unnecessary, as the excess hydrazine suflices to bring all reactants into solution. Nevertheless an additional solvent, such as a lower alcohol or a glycol, may :be useful in certain cases.

From the US. Patent 2,090,429, as well as from Hoppe Seylers Zeitschrift fiir physiologische Chemie, vol. 250, page 7 (1937), and from Helv. Chimica Acta, vol. 26, pages 922928 (1943), it is known that by treating a derivative of the optically active D-lysergic acid or D-isolysergic acid, e.g. one of the naturally occurring ergot alkaloids, 'D,L-isolysergic acid hydrazide, an optically inactive product, results. The optically active compound, D-isolysergic acid hydrazide, which is the only useful one for the synthesis of products of pharmaceutical interest, must subsequently be separated from the racemic mixture with the aid of an optically active acid, e.g. di-(p-toluyl)- L-tartaric acid as demonstrated e.g. in the US. Patent 2,447,214. This procedure is experimentally cumbersome and more than half of the original material is lost, mainly as the useless L-isolysergic acid hydrazide.

On the contrary to this older process, the principal advantage of the new procedure lies in the fact that the cleavage of D-lysergic acid derivatives by hydrazine can be effected Without racemization in a single, simple step. The yields of useful products are in the range of -95% of the theory.

A further advantage of the new process lies in the fact that the reaction proceeds under relatively mild conditions with fewer side reactions occurring concurrently. A reaction temperature of 80 to is as a rule most suitable. The time of reaction at this temperature is in the range of one to a few hours, whereas at e.g. it is only a few minutes. Temperature and time conditions are of course chosen as mild as possible, as with unnecessarily long reaction times and high temperatures partial racemization may occur.

A further technical advantage of the new process is the fact that starting materials may be used which could not be cleaved by hydrazine alone, eg the compounds with R equal to amino, alkylamino or hydroxyalkylamino (e.g. ergometrine).

A further important technical advantage of this invention lies in the fact that it is now possible, starting from l-methyl-D-lysergic acid hydrazide which is obtained according to Example 3, to prepare economically the well known l-methyl-D-lysergic acid-( 1' -hydroxy- -f- -butylamide-(2') of the formula:

C 113 In This compound (Methylsergide) is a potent serotonin antagonist [reference is made to Doepfner and Cerletti, Int. Arch. of Allergy vol. 12, page 39 (1958)] and has already acquired great therapeutical importance in the prophylactic treatment of various forms of headache [reference is made to Friedman and Elkind, J. Amer.

New Process [A] (a) metnylation l-methyl-ergotamine (optically active) Or" the compounds I the 1-methyl-D-lysergic acid hydrazide' and l-methyl-D-isolysergic acid hydrazide are new and are included within the. scope of this invention.

In the following non-limitative examples all temperatures are stated in degrees centigrade andare uncorrected.

DIAGRAM Old Process [13] Ergotamine (opt. active) (a) clearage with hydrazine hydrate rac. mixture of isolysergic acid hydrazides process according to the present invention (1)) separation .of the optical antinodes l l-methyl-D-lysergic acid hydrazide (optically active) (c) corresponding azide (optically active) (d) reaction with butanola mine-(2) new process of the present invention [A] as well as by the old process [B] is represented in the following diagram.

It is easily seen that the present process results in the 4 circumvention of the great loss of material in the form of useless L-compound and in a reduction of the necessary chemical steps by one. The consequence is a considerable saving of time and materials, as well as a further increase in overall yield.

Thus, the new process, for example in preparing the hitherto unknown -1methyl-D-lysergic acid hydrazide, is an important technical advance.

The process in accordance with the invention may, for example, be eifected as follows: One part by weight of compound II in the form of a salt, e.g. ergotamine hydrochloride, is heated with four parts by weight of anhydrous hydrazine for one hour at 90 C. The reaction mixture is then diluted, preferably with water, the excess hydrazine and water distilled off azeotropically, and the residue shaken between aqueous tartaric acid and an inert, water-immiscible solvent, e.g. chloroform or ether. The aqueous phase is made alkaline and the final product taken up in a water immiscible solvent, e.g. chloroform.

Should a compound II, in which R signifies NH or the radical of an alkylamine or hydroxyalkylamine, hav- 1 ing from 1 to 4 carbon atoms inclusive in the alkyl portion, be used, then the reaction mixture, after heating with hydrazine, may be directly diluted with water and extracted with a water-immiscible solvent, e. g. chloroform, if desired, after the addition of ammonia.

The crude product obtained after evaporation of the solvent is generally a mixture of the optically active hydrazides of the lysergic and, predominantly, of the isolysergic acid series, which may be separated in accordance with known methods, e.g. by crystallization and/ or chromatography or by conversion to a salt with a suitable acid.

Compounds I may be used as intermediate products in the production of pharmaceuticals.

L-isoiysergic acid hydrazide (useless) i D-isolysergic acid hydrazide (optically active) (c) corresponding azide (optically active) (d) reaction with butanolamine-(2) D-lysergic acid-(1)-hydr0xy- (+)-butylamide-(2) (optically active) (e) methylation Example 1 1.16 g. of ergotamine hydorchloride are heated with 4 cc. of anhydrous hydrazine for 1 hour to 20 cc. of water are then. added, the water and-thehydrazine hydrate distilled off and the residue shaken between tartaric acid and ether. The bases liberated after making the aqueous phase alkaline are shaken withchloroform and the crude product resulting after evaporation of the chloroform cromatographed on aluminum oxide. The resulting D-isolysergic acid hydrazide is washed into the filtrate with chloroform containing 0.5% of ethanoLi Prisms from methanol/ether. Melting point 202*. [a] =+4-45 (c.=0.5 in pyridine).

A small quantity of D-lysergic acid hydrazide is then- Washed into the filtrate with chloroform containing. 2% of ethanol. Prisms from methanol/ether. Melting point 215. [u] =+lO (c.=,0.5 in pyridine).

Example 2 l g. of isoly-sergic amide hydrochloride is heated with 4 cc. of hydrazine for 50 minutes. to 90, 20cc. of water and 5 cc. of concentrated ammonia then added and the ride in 6.4 cc. of anhydrous hydrazine are heated for 1 hour at 90, the mixture diluted with 50 cc. of water,

the water and the hydrazine hydrate are distilled off and after the addition of a further 6.4 cc. of anhydrous hydrazine the remaining procedure is repeated. The residue is then shaken between a diluted tartaric acid solution and chloroform. The bases liberated after the tartaric acid solution has been made alkaline are shaken with chloroform and the crude product remaining after evaporation of the chloroform is chromatographed on a column of 25 g. of aluminium oxide. l-methyl-D-isolysergic acid hydrazide is washed into the filtrate with chloroform containing 0.5% of ethanol. The compound crystallizes from ethanol in the form of nice leaflets. Melting point 201-204. [a] =+400 (c.=0.5 in pyridine). Kellers colour reaction: blue.

The l-methyl-D-lysergic acid hydrazide is then washed into the filtrate with 1 to 2% of ethanol. Prisms from ethanol. Melting point 194l95. [a] =+14 (c.=0.5 in pyridine). Kellers colour reaction: blue.

Example 4 1 g. of lysergic acid propanolamide (ergometrine) is heated with 5 cc. of anhydrous hydrazine and a solution of 350 mg. of hydrogen bromide in 2 cc. of ethanol to 90 for 1 hour. The reaction mixture is worked up in the manner described in Example 2, the products being D-lysergic acid hydrazide and predominantly D- isolysergic acid hydrazide with the properties indicated in Example 1.

Example 5 A solution of 1 g. of ergotamine is heated with 5 cc. of anhydrous hydrazine and 1 cc. of glacial acetic acid to 120 for 30 minutes. The mixture is worked up as described in Example 1, the product being essentially D-isolysergic acid hydrazide with the properties mentioned.

Example 6 1 g. of lysergic acid amide is heated with 5 cc. of hydrazine in the presence of 500 mg. of methansulfonic acid in 2 cc. of n-butanol for 40 minutes to 100. The products, D-lysergic acid hydrazide and predominantly D-isolysergic acid hydrazide, are isolated as described in Example 1.

What is claimed is:

1. A method for the preparation of optically active compounds of the formula:

wherein R is a member selected from the group consisting of hydrogen, alkyl of 1 to 4 carbon atoms, alkenyl of 3 to 4 carbon atoms, and benzyl, which comprises heating an optically active compound of the formula:

wherein R :has the aforesaid significance and R is a member selected from the group consisting of alkoxy of 1 to 4 carbon atoms, amino, alkylamino, hydr-oxyalkylamino and the tripeptide radicals of the natural waterins-oluble ergot alkaloids at a temperature of to about for a time not substantially in excess of one hour with an excess of anhydrous hydrazine in the presence of at least one equivalent, based on the molar amount of optically active compounds of the Formula II, of a hydrogen ion producing agent, selected from the group consisting of inorganic and organic acids of a pK value smaller than 5.

2. A method for the production of l-methyl-D-lysergic acid hydrazide with the optical rotation of [a] =|-14 (c.=0.5 in pyridine) comprising reacting optically active l-methyl ergotamine at a temperature of 80-135" C. for a time not substantially in excess of one hour with an excess of anhydrous hydrazine in the presence of at least one equivalent of a hydrogen ion producing agent selected from the group consisting of inorganic and organic acids of pK value smaller than 5 and isolating the hydrazide product.

3. A method for the production of l-methyl-D-isolysergic acid hydrazide with the optical rotation of [a] =+400 (c.=0.5 in pyridine) comprising reacting optically active l-methyl-ergotamine at a temperature of 80-135" C. for a time not substantially in excess of one hour with an excess of anhydrous hydrazine in the presence of at least one equivalent of a hydrogen ion producing agent selected from the group consisting of inorganic and organic acids of pK value smaller than 5 and thereafter isolating the hydrazide product.

References Cited by the Examiner UNITED STATES PATENTS 2,447,214 8/ 1948 Stool et al 260285 2,796,419 6/1957 Kornfeld et al. 260-2855 3,085,092 4/1963 Hofmann et al. 260285.5

FOREIGN PATENTS 811,964 4/ 1959 Great Britain.

IRVING MARCUS, Primary Examiner.

NICHOLAS S. RIZZO, Examiner. 

1. A METHOD FO THE PREPARATION OF OPTICALLY ACTIVE COMPOUNDS OF THE FORMULA: 